Guidance for industry on flexible approaches to regulation we are taking during the COVID-19 outbreak.
We are working closely with the Department of Health and Social Care (DHSC) and other healthcare partners and stakeholders to rapidly identify where flexibilities in the regulation of medicines and medical devices may be possible. This is with a view to supporting the healthcare products supply chain and wider response to the coronavirus (COVID-19) outbreak in the UK.
Making use of regulatory flexibilities
Please bear in mind that flexibilities do not displace or diminish any other obligations applicable to the relevant products. Any medicinal product which benefits from these regulatory flexibilities remains subject to marketing authorisation.
Requirements set out for each of the regulatory flexibilities may vary (for example, pre-conditions and notifications). Manufacturers should take great care to meet the relevant requirements and must satisfy themselves that the product remains safe to use before putting a flexibility in place.
None of these flexibilities amount to authorisation or a recommendation by the MHRA for the purposes of Regulations 174 and 345 of the Human Medicines Regulations.
These regulatory flexibilities are:
- temporary and will be kept under review
- offered to protect people’s health in exceptional circumstances
- effective immediately
We have identified areas of flexibility which differ from the EU. These are indicated by an asterisk (*). Please be aware that some UK flexibilities, while aligned with those of the EU, are not limited to treatments for COVID-19 products, but cover the supply of other essential products that have been affected by the outbreak by factors such as travel and transportation restrictions or shortages of starting materials. These are indicated by two asterisks (**).
Scientific advice and reviews (published 1 April 2020)
We are providing expedited scientific advice, and rapid reviews of clinical trials applications to support manufacturers and researchers on potential treatments for COVID-19.
Clinical Trials and Good Clinical Practice (published 1 April 2020)
We have published guidance covering how to manage clinical trials during COVID-19.
Nitrosamine responses (published 1 April 2020, updated 1 February 2021)
In response to review under Article 5(3) of Regulation 726/2004 the deadline for provision of step 1 nitrosamine responses has been extended. For the current status, please refer to Medicines: Marketing Authorisation Holders’ submission of Nitrosamine risk evaluation, risk assessment and confirmatory testing.
QP Declarations (published 16 April 2020) *
COVID-19 is considered to be an exceptional circumstance for QP declarations.
EMA (European Medicines Agency) guidance (EMA/196292/2014) states:
Exceptional circumstances, when an on-site audit is not practical (e.g. atypical actives), are out of scope of the declaration template. An off-site, remote or “paper-based” audit may be justifiable …on a case-by-case basis.
In these cases, a suitable quality system is expected to be applied by the active substance and finished product manufacturers. As a principle, such controls must provide confidence that the active substance is fit for purpose and will not negatively affect the safety and efficacy of the medicinal product. The QP is expected to justify the controls in place on a scientific basis and record a risk assessment on a product specific basis.
Audits of each site…at regular intervals…normally within three years. Justification should be provided if the date since the last audit exceeds this.
Variations and initial applications for products required to maintain continuity of supply (published 16 April 2020)
We will where justified:
- Strongly encourage off-site auditing to review data/documents where possible
- Allow the re-audit window to be extended up to 4 years
- Allow the re-audit window to be extended up to 5 years where supported by an off-site audit
- Allow absence of initial onsite audit where supported by an off-site audit. If the manufacturing site has an EU GMP certificate (or appropriate certification/inspection status from a territory with which the UK/EU shares an appropriately scoped MRA or is an EU “white listed” country) then this should be stated together with any appropriate supporting data.
- Other exceptional circumstances may be referred to the MHRA Regulatory Information Service for consideration on a case-by-case basis.
30-day limit for Type 1B variation replies (published 8 April 2020) *
Suspending the 30-day limit for replies to question on Type 1B variations
DCP (Decentralised Procedure) CMS (Concerned Member State) applications (published 8 April 2020) *
Extending the 30-day national phase for DCP CMS applications. If requested by the company, we will hold the application with the clock off until all documentation is available.
Leaflet mock-ups (published 8 April 2020) *
Waiving the requirement for leaflet mock-ups to be submitted to support variations. Text versions will be accepted and these will be uploaded onto the MHRA Products website. This does not apply to 61(3) applications.
Over-labelling (published 8 April 2020, updated 7 May 2020) *
Considering derogations from labelling requirements and over-labelling of foreign language packs for UK market on a case-by-case basis.
Implementation period for label/leaflet changes (published 8 April 2020) *
Extending the permitted implementation period for label/leaflet changes following a variation from 6 months to 9 months. This does not apply for any significant safety updates.
Expedited assessment of variations and initial applications (published 1 April 2020)**
We are implementing priority and expedited assessment for national variations (including batch-specific variations) and initial marketing authorisation applications that impact the medicines supply chain.
Guidance is in preparation on how to highlight these at the time of submission. Please send notification of requests to expedite to MHRA in advance of submission:
Relaxation of risk minimisation measures (published 7 May 2020, updated 19 May 2020)
Offering urgent review procedure for industry proposals for a temporary relaxation of risk minimisation measures where they place an unnecessary burden on the NHS or shielded patients during the pandemic. This may involve assessment of complex issues and the risk. The benefit balance will need to be reviewed on a case by case basis, with patient safety the top priority.
As an example we have agreed that pregnancy testing as part of a pregnancy prevention plan (PPP) can be done remotely, on a case by case basis and when necessary, as long as the following minimum criteria are met:
- Adequate instruction and support are provided, including where possible supply of the test and a spare or, if this is not possible, provision of a list of acceptable test kits
- The pregnancy tests meet the minimum required sensitivity (25 mIU/mL)
- The result of each pregnancy test is verified by the prescriber, ideally by sending a photograph of the test result. Where this is not possible it should be verified through discussion on the telephone of the result, the kit make, and how it was used.
Where you consider that it is appropriate to use this can you please contact us at email@example.com to discuss before applying this flexibility.
Flexibility in reporting requirement for ICSRs (published 7 May 2020) *
Agreeing with the prioritisation for ICSRs published by the Joint EU Commission, EMA and HMA Questions and answers on regulatory expectations for medicinal products for human use during the COVID-19 pandemic, however requesting that a further category is added at second on the prioritisation list, as follows: ‘submission of other serious ICSRs which reference an impact of the pandemic’ (for example, use of other medicines impacted by COVID-19).
ICSRs (Individual Case Study Reports) (published 16 April 2020)
Follow-up procedures, as outlined in GVP module VI, GVP module VI should be conducted in a risk-proportionate manner and minimise the burden on health care professionals (HCPs), wherever possible.
Prioritisation should be given to:
- align to serious ICSRs
- monitored events of special interest as per the risk management plan
- prospective reports of pregnancy
- those considered important in relation to COVID-19
Risk minimisation measures to ease burden on HCPs (published 16 April 2020)
Waive requirement for evidence of receipt of risk minimisation measures by HCPs.
Flexibility in timelines for surveys on the effectiveness of educational materials involving HCPs.
Postponement of other pharmacovigilance requirements (published 16 April 2020)
Postpone or waive requirement of submission of PSURs for actives authorised only in UK, that is those not on the EURD list. Submission frequencies/dates can be amended accordingly.
Safety variations (published 16 April 2020)
Allow flexibility over submission of national variations/implementation dates (up to 3 months extension) for updates to product information following safety reviews, except for significant public health issues where MAHs will be advised of timelines.
Allow flexibility in accepting extension requests for RFI responses and flexibility to labels and leaflets. This is in terms of waiving requirements to submit mock-ups as part of a variation and extension of the permitted implementation period for label/leaflet changes, following a variation from 6 months to 9 months, with the exception of significant public health issues.
Renewals (published 16 April 2020)
Flexibility in submission date with no automatic lapse of national MAs due to lack of submission of a renewal application.
Other areas (published 16 April 2020)
Flexibility in allowing dissemination of Professional Communications (DHPCs) via email rather than sending hard copies.
Flexibility in allowing dissemination of educational materials via email rather than sending hard copies.
Inspections and good practice
Our guidance on flexibilities in this area (published 1-21 April 2020)
- We have published guidance on exceptional GMP (Good manufacturing practice) flexibilities for medicines manufacturers**
- We have published guidance on approval of GxP documents when working from home
- We are allowing alternative courses of actions for manufacturing or GxP laboratory equipment*
- We have issued exceptional flexibilities on good distribution practice (GDP) to support wholesalers.**
- Routine inspections approach – we are no longer routinely undertaking onsite inspections which are being replaced with desk-based inspections in most cases
- Specials’ licence holders – We are permitting the ‘pack down’ of large packs of licenced medicinal products into smaller quantities for retail sale by pharmacies
- Imported products (3rd countries) – We may implement reduced re-testing where this will significantly delay Qualified Person (QP) certification and batch release (e.g. sterility tests) **
Information for manufacturers of human plasma-derived medicines during the coronavirus (COVID-19) outbreak (published 10 July 2020)
We are working to support manufacturers of human plasma-derived medicines to focus on service continuity during the COVID-19 outbreak, by offering to provide temporary inspection flexibility in exceptional circumstances.
In the case of third country plasma collection sites that have been previously inspected by MHRA, we will implement a control measure in line with EMA recommendation EMA/INS/GMP/534269/2018 “Application of inspection and control measures”. A Statement of Next Inspection (SONI) will be issued, stating the recommended date of the next inspection.
In the case of third country sites that have not been previously inspected, MHRA will take the following action:
- If the plasma collection centre is operated by a parent company that already operates other centres that are included in the manufacturers’ Plasma Master File, MHRA will carry out a distant assessment. A Statement of Next Inspection (SONI) will state the recommended date of the next inspection. If the outcome of the distant assessment does not permit the approval of the plasma collection centre, the application will be put on hold until an on-site inspection is possible.
- If the centre is operated by a parent company that has never previously been inspected or where the parent company is in a compliance management programme the application will be put on hold until an on-site inspection is possible.
How manufacturers and wholesalers should notify us when using flexibilities (published 21 April 2020, updated 10 July 2020)
A dedicated email address has been created for manufacturers and wholesalers to notify the MHRA when using flexibilities. Notifications should be sent to Covid19.GMDP@mhra.gov.uk on a ‘do and tell’ basis.
No prospective MHRA approval is necessary.
The information required is:
- Manufacturing authorisation number and site number
- A description of the regulatory flexibility used
- The reason for using the flexibility
- The anticipated duration of using the flexibility, as date range or ‘ongoing’ if unknown.
- The product name and marketing authorisation number to which the flexibilities are applied (manufacturers only)
- The market to be supplied (if not UK),
When implemented flexibilities impact product supplied to the USA, the FDA should also be notified to CDER-OPQ-Inquiries@fda.hhs.gov. In the case of proposals to ship product from a manufacturing site to another suitably authorised site under quarantine, whilst quality control tests and batch certification at the manufacturer are ongoing, the manufacturer should seek prior approval from FDA via CDER-OPQ-Inquiries@fda.hhs.gov
When re-testing on importation for EU market supply is reduced the notification must also confirm that the competent authority of the relevant market has been notified and no objection has been received.
QP certification (published 1 April 2020)
We will prioritise variations to add replacement QPs to MIA/MIA(IMP), including non-practising or retired QP. QP remote working arrangements will be permitted, where procedures facilitate this approach
Blood components for transfusion
Flexibilities for hospital blood banks (Published 3 April 2020) *
We are offering temporary regulatory flexibility to hospital blood banks to help them focus on service continuity during the COVID-19 outbreak
Audits of Notified Bodies, UK Approved Bodies and manufacturers (published 5 June 2020) **
Where feasible, audits of Notified Bodies, UK Approved Bodies and manufacturers have been delayed. Remote audits and reviews are being considered as alternatives.
Clinical investigations (published 2 April 2020, updated 7 May 2020) *
We have developed an expedited process for Clinical Investigations (CIs) directly relating to COVID-19.
We will maintain a flexible and pragmatic approach to the regulatory requirements for clinical investigations.
- Any amendments to existing clinical investigations as a direct result from COVID-19 will be expedited
- Any new submissions for clinical investigations that will have a direct impact on the COVID-19 emergency will be processed through an expedited review
- Protocol deviations as a result of COVID-19 do not need to be notified to MHRA; however you should maintain good records of these deviations. Unless there is an impact onto patient safety, you do not need to notify MHRA of COVID-19 related deviations. However, all other protocol deviations must be reported to us as normal
Optimised derogations (published 2 April 2020) **
We continue to review and streamline the derogation process. The focus is primarily on critical care devices, COVID-19 testing and personal protective equipment (PPE).
We have engaged with partners to establish clear paths of communication and develop streamlined processes but equally ensure there is appropriate regulatory rigour, where required.
Our aim is to reduce the assessment timeframes significantly and to ensure the process is agile enough to rapidly respond to requests.
Further detail is outlined by our exemptions from Devices regulations during the COVID-19 outbreak.
Expedited advice service for devices (published 2 April 2020)
All COVID-19 enquiries are being prioritised ahead of the Agency’s standard targets.
Exceptional use applications (published 2 April 2020) **
Exceptional use applications are being processed to ensure a continued supply of non-UKCA or non-CE Marked Medical Devices where there is a significant clinical need and where there are no UKCA or CE Marked Devices available.
New specifications (published 2 April 2020)
We have issued specifications for CPAP and ventilators to ensure a continued supply of these critical medical devices during the COVID-19 crisis.